In response to stress, pre-menopausal women are more likely to become depressed than are men, suggesting that being female and exposure to cycling female sex hormones may constitute part of depression vulnerability. Only some women develop depressive illness, however, indicating that women differ in stress sensitivity and depression vulnerability. Rodent models of depression that examine responses of stress-vulnerable vs. stress-resistant females would be valuable to understand the biologic basis of differential stress and depression vulnerability in women but models of depression generally have used male rats as subjects. Preliminary data indicate that Sprague-Dawley female rats are markedly more sensitive to stress than are Long-Evans female rats across several behaviors and biologic indices, including a behavioral model of depression and hypothalamo-pituitary-adrenocortical (HPA) axis responses. These differences in response to stress could be the result of many factors, including actions of estradiol on brains that are different and line differences in how stress affects estradiol levels or estrus cycling. Estradiol is the major sex hormone with behavioral and biologic actions in females. Estradiol interacts with stress-sensitive brain systems (i.e., serotonergic, dopaminergic) that control the behaviors under study. Estradiol also interacts with the HPA axis. Therefore, examining estradiol's role in stress responding of stress-sensitive female rats (Sprague-Dawley) and stress-resistant female rats (Long-Evans) is a critical step toward understanding why some females are more vulnerable to stress and depression than others. Behavioral and corticosterone responses of Sprague-Dawley and Long-Evans females that are intact, ovariectomized, or ovariectomized with estradiol replacement will be evaluated in response to daily restraint stress. Responses also will be compared with intact male rats. To determine whether female line differences in response to stress are the result of changes in estrus cycling or line differences in estradiol levels, estrus cycle and estradiol levels of intact females also will be assessed.